The present invention is directed to G-protein coupled receptor (GPCR) agonists. In particular, the present invention is directed to agonists of GPR116 that are useful as regulators of satiety, e.g. for the treatment of obesity, and for the treatment of diabetes.
Obesity is characterized by an excessive adipose tissue mass relative to body size. Clinically, body fat mass is estimated by the body mass index (BMI; weight(kg)/height(m)2), or waist circumference. Individuals are considered obese when the BMI is greater than 30 and there are established medical consequences of being overweight. It has been an accepted medical view for some time that an increased body weight, especially as a result of abdominal body fat, is associated with an increased risk for diabetes, hypertension, heart disease, and numerous other health complications, such as arthritis, stroke, gallbladder disease, muscular and respiratory problems, back pain and even certain cancers.
Pharmacological approaches to the treatment of obesity have been mainly concerned with reducing fat mass by altering the balance between energy intake and expenditure. Many studies have clearly established the link between adiposity and the brain circuitry involved in the regulation of energy homeostasis. Direct and indirect evidence suggest that serotonergic, dopaminergic, adrenergic, cholinergic, endocannabinoid, opioid, and histaminergic pathways in addition to many neuropeptide pathways (e.g. neuropeptide Y and melanocortins) are implicated in the central control of energy intake and expenditure. Hypothalamic centres are also able to sense peripheral hormones involved in the maintenance of body weight and degree of adiposity, such as insulin and leptin, and fat tissue derived peptides.
Drugs aimed at the pathophysiology associated with insulin dependent Type I diabetes and non-insulin dependent Type II diabetes have many potential side effects and do not adequately address the dyslipidaemia and hyperglycaemia in a high proportion of patients. Treatment is often focused at individual patient needs using diet, exercise, hypoglycaemic agents and insulin, but there is a continuing need for novel antidiabetic agents, particularly ones that may be better tolerated with fewer adverse effects.
Similarly, metabolic syndrome (syndrome X) which is characterized by hypertension and its associated pathologies including atherosclerosis, lipidemia, hyperlipidemia and hypercholesterolemia have been associated with decreased insulin sensitivity which can lead to abnormal blood sugar levels when challenged. Myocardial ischemia and microvascular disease is an established morbidity associated with untreated or poorly controlled metabolic syndrome.
There is a continuing need for novel antiobesity and antidiabetic agents, particularly ones that are well tolerated with few adverse effects.
GPR116 is a GPCR identified as SNORF25 in WO00/50562 which discloses both the human and rat receptors, U.S. Pat. No. 6,468,756 also discloses the mouse receptor (accession numbers: AAN95194 (human), AAN95195 (rat) and ANN95196 (mouse)).
In humans, GPR116 is expressed in the pancreas, small intestine, colon and adipose tissue. The expression profile of the human GPR116 receptor indicates its potential utility as a target for the treatment of obesity and diabetes.
Williams J. P., Combinatorial Chemistry & High Throughput Screening, 2000, 3, 43-50 discloses the compounds 4-(5-piperidin-4-yl-[1,2,4]oxadiazol-3-yl)pyridine and 4-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-yl)piperidine-1-carboxylic acid tbutyl ester, synthesised as part of a compound library designed to identify dopamine D4 ligands.
The compounds 4-[5-(4-butylcyclohexyl)-[1,2,4]oxadiazol-3-yl]pyridine and 3-[5-(4-propylcyclohexyl)-[1,2,4]oxadiazol-3-yl]pyridine (Chem Div) and 3-[5-(4-butylcyclohexyl)-[1,2,4]oxadiazol-3-yl]pyridine (Chembridge) are/were commercially available. No pharmaceutical utility has been suggested for these compounds.
The present invention relates to agonists of GPR116 which are useful as peripheral regulators of satiety, e.g. for the treatment of obesity, and for the treatment of diabetes.